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Papers by Bram Dierckx
Nederlands Tijdschrift voor Geneeskunde, 2019
Nederlands tijdschrift voor geneeskunde, 2019
Antipsychotics have an important role in the treatment of children with severe behavioural proble... more Antipsychotics have an important role in the treatment of children with severe behavioural problems. Use of antipsychotics in the Netherlands increased dramatically up until 2009. In recent years, however, the side-effects of antipsychotics in children have received increasing attention. One in eight children uses antipsychotics for at least 4 years. This long-term use increases the risk of side-effects, but these are often not optimally monitored. There should also be more attention for the timely tapering off of antipsychotics in children.
Journal of child and adolescent psychopharmacology, 2021
Objectives: Numerous studies have examined determinants contributing to methylphenidate adherence... more Objectives: Numerous studies have examined determinants contributing to methylphenidate adherence and persistence, but these were mainly conducted in adults. These determinants are likely to be different in children as they usually rely on their parents to provide them with the care they need. The objective was to study child and family characteristics as determinants of methylphenidate adherence and persistence in children. Methods: The study population consists of 307 children from the Generation R Study in the Netherlands, who had at least one dispensing record of methylphenidate until the age of 16 years. Adherence was defined as a medication possession ratio ≥0.80 up to 2 years after treatment initiation. Persistence was defined as the duration of treatment until a discontinuation period of ≥6 months. Family and child characteristics were tested as determinants of adherence with multivariable logistic regression analysis. Persistence was evaluated using a Kaplan-Meier analysis....
Background: Preoperative anxiety in children is highly prevalent and is associated with adverse o... more Background: Preoperative anxiety in children is highly prevalent and is associated with adverse outcomes. Existing psychosocial interventions to reduce preoperative anxiety are often aimed at distraction and are of limited efficacy. Gradual exposure is a far more effective way to reduce anxiety. Virtual reality (VR) provides a unique opportunity to gradually expose children to all aspects of the operating theater. Objective: The aims of our study are (1) to develop a virtual reality exposure (VRE) tool to prepare children psychologically for surgery; and (2) to examine the efficacy of the VRE tool in a randomized controlled trial (RCT), in which VRE will be compared to care as usual (CAU). Methods: The VRE tool is highly realistic and resembles the operating room environment accurately. With this tool, children will not only be able to explore the operating room environment, but also get accustomed to general anesthesia procedures. The PREoperative Virtual reality Intervention to En...
Disclaimer/Complaints regulations If you believe that digital publication of certain material inf... more Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
Expert Opinion on Drug Safety, 2020
Introduction The use of psychotropic drugs in children and adolescents is widespread but associat... more Introduction The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known. Areas covered This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants, and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. Sixty-seven eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies were not of sufficient quality. For 11 psychotropic drugs, a relationship between...
Anxiety disorders are highly prevalent and debilitating psychiatric conditions, which often remai... more Anxiety disorders are highly prevalent and debilitating psychiatric conditions, which often remain unrecognised and untreated. However, left untreated, anxiety disorders often persist and can contribute to the development of other psychiatric disorders. Therefore, early detection and subsequent intervention are important. Information on the age of onset (AOO) of anxiety disorders could be informative for the timing of prevention strategies.
Tijdschrift voor psychiatrie, 2018
ACHTERGROND Het fragiele-X-syndroom (fxs) is de meest voorkomende erfelijke oorzaak van een verst... more ACHTERGROND Het fragiele-X-syndroom (fxs) is de meest voorkomende erfelijke oorzaak van een verstandelijke beperking en autismespectrumstoornissen. Een gerichte therapie ontbreekt vooralsnog. De afgelopen decennia brachten een explosie aan kennis over de betrokken moleculaire processen en daarmee potentiele aangrijpingspunten voor gerichte therapie. DOEL Een overzicht geven van de ontwikkeling van gerichte therapie voor fxs. METHODE Een aantal belangrijke publicaties werd verzameld en op een rij gezet. RESULTATEN Preklinische diermodelonderzoeken tonen veelbelovende resultaten van gerichte interventies, maar vertaling naar de kliniek is vooralsnog teleurstellend. CONCLUSIE Een gerichte therapie voor fxs is nodig en zou mogelijk kunnen worden toegepast bij andere oorzaken van autisme en verstandelijke beperking. Aspecten op het gebied van translatie, studieopzet en uitkomstmaten spelen mogelijk een rol bij de teleurstellende resultaten. Voor de klinische implementatie van toekomstige...
Magnetic resonance imaging (MRI) procedures often evoke anxiety in children. Further, anxious chi... more Magnetic resonance imaging (MRI) procedures often evoke anxiety in children. Further, anxious children may be less likely to participate in MRI research, leading to a possible selection bias, and may be more likely to move during image acquisition, resulting in lower image quality and possible information bias. Therefore, state anxiety is problematic for functional and structural MRI studies. Children with behavioral problems, such as internalizing and externalizing behaviors, may be more likely to experience state anxiety prior to and during MRI scanning. Therefore, our first aim was to investigate the relationship between internalizing/externalizing behavior and children’s MRI-related state anxiety. Our second aim was to investigate the relationship between internalizing and externalizing behavior and MRI research participation. Our final aim was to investigate the effect of internalizing and externalizing behavior as well as MRI-related anxiety on image quality in children. We in...
European Child & Adolescent Psychiatry
Antipsychotic-induced weight gain is a major health concern in children and adolescents. The aim ... more Antipsychotic-induced weight gain is a major health concern in children and adolescents. The aim of this study was to identify risk factors for weight gain during short-, middle- and long-term treatment with antipsychotic drugs in this young population. We analysed a combined prospective and a retrospective observational cohort of Dutch children and adolescents, starting with risperidone, aripiprazole or pipamperone treatment. Linear mixed models were used to test whether sex, age, baseline body-mass-index (BMI) z score, type of antipsychotic, dose equivalent/kg, duration of use, previous antipsychotic use, ethnicity, physical exercise, IQ, concomitant medication, and psychiatric classification predicted the BMI z score for a follow-up of 52 weeks. A total of 144 patients were included with a median [interquartile range ([IQR)] age of 9 (4) years and median follow-up of 30 (73) weeks. During the complete follow-up, the median (IQR) weight gain was 0.37 (0.95) BMI z score points. An...
British Journal of Clinical Pharmacology
Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents w... more Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. Methods: Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during followup. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM ®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models. Results: A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .
Journal of Clinical Psychology in Medical Settings
In children, intense levels of anxiety during anesthetic induction are associated with a higher r... more In children, intense levels of anxiety during anesthetic induction are associated with a higher risk of pain, poor recovery, and emergence delirium. Therefore, it is important to identify these high-risk children at hospital arrival. The current study examined internalizing behavior (Child Behavior Checklist, CBCL) and state anxiety measures (modified Yale Preoperative Anxiety Scale, mYPAS, and State Trait Anxiety Inventory for Children, STAIC) at hospital arrival as predictors of anxiety during induction of anesthesia. One hundred children (aged 4 to 12 years) undergoing elective daycare surgery were included. The STAIC and mYPAS at hospital arrival were significant predictors of anxiety during induction, whereas CBCL was not. The STAIC state form at hospital arrival was the strongest predictor and could be used to identify children who will experience intense levels of anxiety during anesthetic induction, with sufficient to good diagnostic accuracy. Using the STAIC at hospital arr...
European Journal of Anaesthesiology
BACKGROUND Pre-operative anxiety in children is very common and is associated with adverse outcom... more BACKGROUND Pre-operative anxiety in children is very common and is associated with adverse outcomes. OBJECTIVE The aim of this study was to investigate if virtual reality exposure (VRE) as a preparation tool for elective day care surgery in children is associated with lower levels of anxiety, pain and emergence delirium compared with a control group receiving care as usual (CAU). DESIGN A randomised controlled single-blind trial. SETTING A single university children's hospital in the Netherlands from March 2017 to October 2018. PATIENTS Two-hundred children, 4 to 12 years old, undergoing elective day care surgery under general anaesthesia. INTERVENTION On the day of surgery, children receiving VRE were exposed to a realistic child-friendly immersive virtual version of the operating theatre, so that they could get accustomed to the environment and general anaesthesia procedures. MAIN OUTCOME MEASURES The primary outcome was anxiety during induction of anaesthesia (modified Yale Preoperative Anxiety Scale, mYPAS). Secondary outcomes were self-reported anxiety, self-reported and observed pain, emergence delirium, need for rescue analgesia (morphine) and parental anxiety. RESULTS A total of 191 children were included in the analysis. During induction of anaesthesia, mYPAS levels (median [IQR] were similar in VRE, 40.0 [28.3 to 58.3] and CAU, 38.3 [28.3 to 53.3]; P ¼ 0.862). No differences between groups were found in self-reported anxiety, pain, emergence delirium or parental anxiety. However, after adenoidectomy/tonsillectomy, children in the VRE condition needed rescue analgesia significantly less often (55.0%) than in the CAU condition (95.7%) (P ¼ 0.002). CONCLUSION In children undergoing elective day care surgery, VRE did not have a beneficial effect on anxiety, pain, emergence delirium or parental anxiety. However, after more painful surgery, children in the VRE group needed rescue analgesia significantly less often, a clinically important finding because of the side effects associated with analgesic drugs. Options for future research are to include children with higher levels of anxiety and pain and to examine the timing and duration of VRE.
Journal of Child and Adolescent Psychopharmacology
OBJECTIVES The use of antipsychotic drugs by youth is associated with serious side effects, espec... more OBJECTIVES The use of antipsychotic drugs by youth is associated with serious side effects, especially when prescribed in higher dosages and for a longer period. Despite this, little is known about recent trends in the dosages and duration of use of antipsychotic drugs in children and adolescents. The aim of this study was to describe trends in prevalence, incidence, dosages, duration of use, and preceding psychotropic medication in Dutch youth who had been prescribed antipsychotic drugs from 2005 to 2015. METHODS We analyzed 84,828 antipsychotic prescriptions of youths aged 0-19 years between 2005 and 2015, derived from a large Dutch community pharmacy-based prescription database (IADB.nl). RESULTS Since a peak of 9.8 users per 1000 youths in 2009, prevalence rates stabilized. Dosages in milligram per kilogram declined for the most frequently prescribed antipsychotic drugs during the study period. The median duration of use was 6.0 (95% CI 5.4-6.6) months. Boys used antipsychotic drugs significantly longer than girls, with a median of 6.9 (95% CI 6.1-7.7) versus 4.6 (95% CI 3.9-5.3) months (p < 0.01). Of the youths prescribed antipsychotics, 12.4% used them for at least 48 months. The majority of youths had used other psychotropic agents in the year before the start of an antipsychotic drug (62.4% in 2005 and 64.7% in 2015). CONCLUSIONS Despite a stabilization of usage rates and decline in dosages and duration of use, one in eight youths still used antipsychotic drugs for 4 years or longer. A substantial share of youths may, therefore, be at high risk for serious side effects.
Anesthesia & Analgesia
M edical procedures often evoke pain, distress, and anxiety. 1 Especially in children, these feel... more M edical procedures often evoke pain, distress, and anxiety. 1 Especially in children, these feelings not only severely affect comfort levels during medical procedures but are also associated with adverse consequences, such as attempts to escape, 2 poor recovery, 3 eating and sleeping disturbances, 3 and posttraumatic stress symptoms. 4 Furthermore, as pain and anxiety can lead to avoidance of health care, 5,6 interventions are needed to address pain and anxiety in pediatric patients. Distraction is a commonly applied intervention during medical procedures. For example, the use of music 7,8 and movies 9,10 has been proven efficacious in reducing pain and anxiety. Virtual reality (VR) is a relatively new technique to provide distraction and might be more effective than traditional methods. VR consists of a computer-generated environment, in which orientation and 3-dimensional interaction are possible. This environment is projected right in front of the user's eyes via advanced head-mounted displays (HMDs), including a wide field of view and motion tracking systems. 11 VR can create full immersion, which is a feeling of presence in the virtual environment. 11,12 Importantly, more immersion is related to more pain reduction, because BACKGROUND: Medical procedures often evoke pain and anxiety in pediatric patients. Virtual reality (VR) is a relatively new intervention that can be used to provide distraction during, or to prepare patients for, medical procedures. This meta-analysis is the first to collate evidence on the effectiveness of VR on reducing pain and anxiety in pediatric patients undergoing medical procedures. METHODS: On April 25, 2018, we searched EMBASE, MEDLINE, CENTRAL, PubMed, Web of Science, and PsycINFO with the keywords "VR," "children," and "adolescents." Studies that applied VR in a somatic setting with participants ≤21 years of age were included. VR was defined as a fully immersive 3-dimensional environment displayed in surround stereoscopic vision on a head-mounted display (HMD). We evaluated pain and anxiety outcomes during medical procedures in VR and standard care conditions. RESULTS: We identified 2889 citations, of which 17 met our inclusion criteria. VR was applied as distraction (n = 16) during venous access, dental, burn, or oncological care or as exposure (n = 1) before elective surgery under general anesthesia. The effect of VR was mostly studied in patients receiving burn care (n = 6). The overall weighted standardized mean difference (SMD) for VR was 1.30 (95% CI, 0.68-1.91) on patient-reported pain (based on 14 studies) and 1.32 (95% CI, 0.21-2.44) on patient-reported anxiety (based on 7 studies). The effect of VR on pediatric pain was also significant when observed by caregivers (SMD = 2.08; 95% CI, 0.55-3.61) or professionals (SMD = 3.02; 95% CI, 0.79-2.25). For anxiety, limited observer data were available. CONCLUSIONS: VR research in pediatrics has mainly focused on distraction. Large effect sizes indicate that VR is an effective distraction intervention to reduce pain and anxiety in pediatric patients undergoing a wide variety of medical procedures. However, further research on the effect of VR exposure as a preparation tool for medical procedures is needed because of the paucity of research into this field.
Critical Care
Backgrounds: Reports of increasing incidence rates of delirium in critically ill children are rea... more Backgrounds: Reports of increasing incidence rates of delirium in critically ill children are reason for concern. We evaluated the measurement properties of the pediatric delirium component (PD-scale) of the Sophia Observation Withdrawal Symptoms scale Pediatric Delirium scale (SOS-PD scale). Methods: In a multicenter prospective observational study in four Dutch pediatric ICUs (PICUs), patients aged ≥ 3 months and admitted for ≥ 48 h were assessed with the PD-scale thrice daily. Criterion validity was assessed: if the PD-scale score was ≥ 4, a child psychiatrist clinically assessed the presence or absence of PD according to the Diagnostic and statistical manual of mental disorders (DSM)-IV. In addition, the child psychiatrist assessed a randomly selected group to establish the false-negative rate. The construct validity was assessed by calculating the Pearson coefficient (r p) for correlation between the PD-scale and Cornell Assessment Pediatric Delirium (CAP-D) scores. Interrater reliability was determined by comparing paired nurse-researcher PD-scale assessments and calculating the intraclass correlation coefficient (ICC). Results: Four hundred eighty-five patients with a median age of 27.0 months (IQR 8-102) were included, of whom 48 patients were diagnosed with delirium by the child psychiatrist. The PD-scale had overall sensitivity of 92.3% and specificity of 96.5% compared to the psychiatrist diagnosis for a cutoff score ≥4 points. The r p between the PD-scale and the CAP-D was 0.89 (CI 95%, 0.82-0.93; p < 0.001). The ICC of 75 paired nurse-researcher observations was 0.99 (95% CI, 0.98-0.99). Conclusions: The PD-scale has good reliability and validity for early screening of PD in critically ill children. It can be validly and reliably used by nurses to this aim.
Therapeutic Drug Monitoring
To the Editors: We thank Peter Zweipfenning for his comments and remarks about our article by Klo... more To the Editors: We thank Peter Zweipfenning for his comments and remarks about our article by Kloosterboer et al1 entitled “Dried blood spot analysis for therapeutic drug monitoring of antipsychotics: drawbacks of its clinical application.” We agree that the conversion of dried blood spot (DBS) concentrations to estimated plasma concentrations is essential for clinical interpretation. First, Zweipfenning points out the use of the EMA guideline Bioanalytical Method Validation.2 This guideline focuses on the validation of bioanalytical methods in general and was indeed not developed specifically for DBS method validation. New regulatory guidelines finally start recognizing DBS as a relevant matrix only until recently.3 Unfortunately, to our knowledge, currently, there is no specific guideline with explicit criteria for the clinical validation of DBS methods. The EMA guideline, however, clearly addresses the requirements for crossvalidation (see section 4.3., page 10), ie, the comparison of data obtained from different methods. As our clinical validation study compares the DBS sampling method and venous sampling method, the EMA criteria are applicable. These criteria have also been used for DBS method validation in the literature previously.4 An international working group, with participation of the corresponding author, is currently developing a guideline for clinical validation of DBS methods. Second, the use of formula 1 is questioned. We agree that this formula can only be applied when the partition into blood cells is negligible,5 as is explained in our article. A low blood:serum ratio and high protein binding correspond to a negligible concentration in red blood cells, which both apply to the antipsychotics under study. The blood:serum ratios were previously reported by Patteet et al, as referenced in our article under no. 10. In this study, a blood:serum ratio of 0.6 for risperidone, 0.7 for its metabolite, and 0.7 for aripiprazole was reported.6 In general, a blood:serum ratio of 0.6–0.7 can be considered low because a theoretical range of 0.3–2 can be expected.7 We anticipate that the metabolite of aripiprazole has a similar affinity to blood cells because its log P value is comparable and the molecular structure is nearly identical to aripiprazole.8 The same probably applies for pipamperone because all antipsychotics are analyzed in plasma and have similar properties. Furthermore, Peter Zweipfenning elaborates about the margin of error in this ratio. The confidence intervals in the before mentioned study vary between 0 and 0.1 and can thus be interpreted as a low margin of error. Therefore, in our opinion, the blood:serum ratios, in combination with high protein binding, justify the use of formula 1. This formula has been applied in the same way in DBS validation studies previously.9
Therapeutic drug monitoring, Jun 1, 2018
Dried blood spot (DBS) sampling offers a minimally invasive sampling method for therapeutic drug ... more Dried blood spot (DBS) sampling offers a minimally invasive sampling method for therapeutic drug monitoring of antipsychotics. To facilitate implementation in clinical practice, the aim of this study was to perform a clinical validation study of a DBS method for quantification of risperidone, aripiprazole, pipamperone, and their major metabolites 9-OH risperidone and dehydro-aripiprazole in a real-life, clinical setting. Paired DBS and venous plasma samples were analyzed (n = 35 for risperidone, n = 21 for aripiprazole, n = 21 for pipamperone). Estimated plasma concentrations were calculated from DBS concentrations based on hematocrit and/or Deming regression formulas. Deming regression and Bland-Altman analyses were used to determine the agreement between the calculated and measured plasma concentrations. For Bland-Altman analysis, the following acceptance limit was used: for a minimum of 67% of the samples, the difference of the 2 measurements should be within 20% of their mean. T...
Journal of affective disorders, Apr 1, 2018
Anxiety disorders are highly prevalent during adolescence. Although literature points out that an... more Anxiety disorders are highly prevalent during adolescence. Although literature points out that anxiety symptoms are related to problems in social and academic functioning, the extent of these problems among adolescents with clinical anxiety disorders has not been systematically reviewed before. Electronic databases were searched up to October 2017, with keywords representing anxiety disorders, adolescents, and social or academic functioning. The inclusion criteria were studies with a sample of adolescents (10-19 years) with anxiety disorders that provided data regarding their social or academic functioning. 3431 studies were examined, of which 19 met the inclusion criteria. Adolescents with anxiety disorders had a lower social competence relative to their healthy peers. They reported more negativity within interpersonal relationships, higher levels of loneliness, and victimization. Most adolescents with anxiety disorders felt impaired at school, however, findings of their average sc...
Therapeutic Drug Monitoring
Background: Risperidone, aripiprazole, and pipamperone are antipsychotic drugs frequently prescri... more Background: Risperidone, aripiprazole, and pipamperone are antipsychotic drugs frequently prescribed for the treatment of comorbid behavioral problems in children with autism spectrum disorders. Therapeutic drug monitoring (TDM) could be useful to decrease side effects and to improve patient outcome. Dried blood spot (DBS) sample collection seems to be an attractive technique to develop TDM of these drugs in a pediatric population. The aim of this work was to develop and validate a DBS assay suitable for TDM and home sampling. Methods: Risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone were extracted from DBS and analyzed by ultra–high-performance liquid chromatography–tandem mass spectrometry using a C18 reversed-phase column with a mobile phase consisting of ammonium acetate/formic acid in water or methanol. The suitability of DBS for TDM was assessed by studying the influence of specific parameters: extraction solution, EDTA carryover, hematocrit, punching location, spot volume, and hemolysis. The assay was validated with respect to conventional guidelines for bioanalytical methods. Results: The method was linear, specific without any critical matrix effect, and with a mean recovery around 90%. Accuracy and imprecision were within the acceptance criteria in samples with hematocrit values from 30% to 45%. EDTA or hemolysis did not skew the results, and no punching carryover was observed. No significant influence of the spot volume or the punch location was observed. The antipsychotics were all stable in DBS stored 10 days at room temperature and 1 month at 4 or −80°C. The method was successfully applied to quantify the 3 antipsychotics and their metabolites in patient samples. Conclusions: A UHPLC-MS/MS method has been successfully validated for the simultaneous quantification of risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone in DBS. The assay provided good analytical performances for TDM and clinical research applications.
Nederlands Tijdschrift voor Geneeskunde, 2019
Nederlands tijdschrift voor geneeskunde, 2019
Antipsychotics have an important role in the treatment of children with severe behavioural proble... more Antipsychotics have an important role in the treatment of children with severe behavioural problems. Use of antipsychotics in the Netherlands increased dramatically up until 2009. In recent years, however, the side-effects of antipsychotics in children have received increasing attention. One in eight children uses antipsychotics for at least 4 years. This long-term use increases the risk of side-effects, but these are often not optimally monitored. There should also be more attention for the timely tapering off of antipsychotics in children.
Journal of child and adolescent psychopharmacology, 2021
Objectives: Numerous studies have examined determinants contributing to methylphenidate adherence... more Objectives: Numerous studies have examined determinants contributing to methylphenidate adherence and persistence, but these were mainly conducted in adults. These determinants are likely to be different in children as they usually rely on their parents to provide them with the care they need. The objective was to study child and family characteristics as determinants of methylphenidate adherence and persistence in children. Methods: The study population consists of 307 children from the Generation R Study in the Netherlands, who had at least one dispensing record of methylphenidate until the age of 16 years. Adherence was defined as a medication possession ratio ≥0.80 up to 2 years after treatment initiation. Persistence was defined as the duration of treatment until a discontinuation period of ≥6 months. Family and child characteristics were tested as determinants of adherence with multivariable logistic regression analysis. Persistence was evaluated using a Kaplan-Meier analysis....
Background: Preoperative anxiety in children is highly prevalent and is associated with adverse o... more Background: Preoperative anxiety in children is highly prevalent and is associated with adverse outcomes. Existing psychosocial interventions to reduce preoperative anxiety are often aimed at distraction and are of limited efficacy. Gradual exposure is a far more effective way to reduce anxiety. Virtual reality (VR) provides a unique opportunity to gradually expose children to all aspects of the operating theater. Objective: The aims of our study are (1) to develop a virtual reality exposure (VRE) tool to prepare children psychologically for surgery; and (2) to examine the efficacy of the VRE tool in a randomized controlled trial (RCT), in which VRE will be compared to care as usual (CAU). Methods: The VRE tool is highly realistic and resembles the operating room environment accurately. With this tool, children will not only be able to explore the operating room environment, but also get accustomed to general anesthesia procedures. The PREoperative Virtual reality Intervention to En...
Disclaimer/Complaints regulations If you believe that digital publication of certain material inf... more Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
Expert Opinion on Drug Safety, 2020
Introduction The use of psychotropic drugs in children and adolescents is widespread but associat... more Introduction The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known. Areas covered This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants, and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. Sixty-seven eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies were not of sufficient quality. For 11 psychotropic drugs, a relationship between...
Anxiety disorders are highly prevalent and debilitating psychiatric conditions, which often remai... more Anxiety disorders are highly prevalent and debilitating psychiatric conditions, which often remain unrecognised and untreated. However, left untreated, anxiety disorders often persist and can contribute to the development of other psychiatric disorders. Therefore, early detection and subsequent intervention are important. Information on the age of onset (AOO) of anxiety disorders could be informative for the timing of prevention strategies.
Tijdschrift voor psychiatrie, 2018
ACHTERGROND Het fragiele-X-syndroom (fxs) is de meest voorkomende erfelijke oorzaak van een verst... more ACHTERGROND Het fragiele-X-syndroom (fxs) is de meest voorkomende erfelijke oorzaak van een verstandelijke beperking en autismespectrumstoornissen. Een gerichte therapie ontbreekt vooralsnog. De afgelopen decennia brachten een explosie aan kennis over de betrokken moleculaire processen en daarmee potentiele aangrijpingspunten voor gerichte therapie. DOEL Een overzicht geven van de ontwikkeling van gerichte therapie voor fxs. METHODE Een aantal belangrijke publicaties werd verzameld en op een rij gezet. RESULTATEN Preklinische diermodelonderzoeken tonen veelbelovende resultaten van gerichte interventies, maar vertaling naar de kliniek is vooralsnog teleurstellend. CONCLUSIE Een gerichte therapie voor fxs is nodig en zou mogelijk kunnen worden toegepast bij andere oorzaken van autisme en verstandelijke beperking. Aspecten op het gebied van translatie, studieopzet en uitkomstmaten spelen mogelijk een rol bij de teleurstellende resultaten. Voor de klinische implementatie van toekomstige...
Magnetic resonance imaging (MRI) procedures often evoke anxiety in children. Further, anxious chi... more Magnetic resonance imaging (MRI) procedures often evoke anxiety in children. Further, anxious children may be less likely to participate in MRI research, leading to a possible selection bias, and may be more likely to move during image acquisition, resulting in lower image quality and possible information bias. Therefore, state anxiety is problematic for functional and structural MRI studies. Children with behavioral problems, such as internalizing and externalizing behaviors, may be more likely to experience state anxiety prior to and during MRI scanning. Therefore, our first aim was to investigate the relationship between internalizing/externalizing behavior and children’s MRI-related state anxiety. Our second aim was to investigate the relationship between internalizing and externalizing behavior and MRI research participation. Our final aim was to investigate the effect of internalizing and externalizing behavior as well as MRI-related anxiety on image quality in children. We in...
European Child & Adolescent Psychiatry
Antipsychotic-induced weight gain is a major health concern in children and adolescents. The aim ... more Antipsychotic-induced weight gain is a major health concern in children and adolescents. The aim of this study was to identify risk factors for weight gain during short-, middle- and long-term treatment with antipsychotic drugs in this young population. We analysed a combined prospective and a retrospective observational cohort of Dutch children and adolescents, starting with risperidone, aripiprazole or pipamperone treatment. Linear mixed models were used to test whether sex, age, baseline body-mass-index (BMI) z score, type of antipsychotic, dose equivalent/kg, duration of use, previous antipsychotic use, ethnicity, physical exercise, IQ, concomitant medication, and psychiatric classification predicted the BMI z score for a follow-up of 52 weeks. A total of 144 patients were included with a median [interquartile range ([IQR)] age of 9 (4) years and median follow-up of 30 (73) weeks. During the complete follow-up, the median (IQR) weight gain was 0.37 (0.95) BMI z score points. An...
British Journal of Clinical Pharmacology
Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents w... more Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. Methods: Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during followup. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM ®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models. Results: A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .
Journal of Clinical Psychology in Medical Settings
In children, intense levels of anxiety during anesthetic induction are associated with a higher r... more In children, intense levels of anxiety during anesthetic induction are associated with a higher risk of pain, poor recovery, and emergence delirium. Therefore, it is important to identify these high-risk children at hospital arrival. The current study examined internalizing behavior (Child Behavior Checklist, CBCL) and state anxiety measures (modified Yale Preoperative Anxiety Scale, mYPAS, and State Trait Anxiety Inventory for Children, STAIC) at hospital arrival as predictors of anxiety during induction of anesthesia. One hundred children (aged 4 to 12 years) undergoing elective daycare surgery were included. The STAIC and mYPAS at hospital arrival were significant predictors of anxiety during induction, whereas CBCL was not. The STAIC state form at hospital arrival was the strongest predictor and could be used to identify children who will experience intense levels of anxiety during anesthetic induction, with sufficient to good diagnostic accuracy. Using the STAIC at hospital arr...
European Journal of Anaesthesiology
BACKGROUND Pre-operative anxiety in children is very common and is associated with adverse outcom... more BACKGROUND Pre-operative anxiety in children is very common and is associated with adverse outcomes. OBJECTIVE The aim of this study was to investigate if virtual reality exposure (VRE) as a preparation tool for elective day care surgery in children is associated with lower levels of anxiety, pain and emergence delirium compared with a control group receiving care as usual (CAU). DESIGN A randomised controlled single-blind trial. SETTING A single university children's hospital in the Netherlands from March 2017 to October 2018. PATIENTS Two-hundred children, 4 to 12 years old, undergoing elective day care surgery under general anaesthesia. INTERVENTION On the day of surgery, children receiving VRE were exposed to a realistic child-friendly immersive virtual version of the operating theatre, so that they could get accustomed to the environment and general anaesthesia procedures. MAIN OUTCOME MEASURES The primary outcome was anxiety during induction of anaesthesia (modified Yale Preoperative Anxiety Scale, mYPAS). Secondary outcomes were self-reported anxiety, self-reported and observed pain, emergence delirium, need for rescue analgesia (morphine) and parental anxiety. RESULTS A total of 191 children were included in the analysis. During induction of anaesthesia, mYPAS levels (median [IQR] were similar in VRE, 40.0 [28.3 to 58.3] and CAU, 38.3 [28.3 to 53.3]; P ¼ 0.862). No differences between groups were found in self-reported anxiety, pain, emergence delirium or parental anxiety. However, after adenoidectomy/tonsillectomy, children in the VRE condition needed rescue analgesia significantly less often (55.0%) than in the CAU condition (95.7%) (P ¼ 0.002). CONCLUSION In children undergoing elective day care surgery, VRE did not have a beneficial effect on anxiety, pain, emergence delirium or parental anxiety. However, after more painful surgery, children in the VRE group needed rescue analgesia significantly less often, a clinically important finding because of the side effects associated with analgesic drugs. Options for future research are to include children with higher levels of anxiety and pain and to examine the timing and duration of VRE.
Journal of Child and Adolescent Psychopharmacology
OBJECTIVES The use of antipsychotic drugs by youth is associated with serious side effects, espec... more OBJECTIVES The use of antipsychotic drugs by youth is associated with serious side effects, especially when prescribed in higher dosages and for a longer period. Despite this, little is known about recent trends in the dosages and duration of use of antipsychotic drugs in children and adolescents. The aim of this study was to describe trends in prevalence, incidence, dosages, duration of use, and preceding psychotropic medication in Dutch youth who had been prescribed antipsychotic drugs from 2005 to 2015. METHODS We analyzed 84,828 antipsychotic prescriptions of youths aged 0-19 years between 2005 and 2015, derived from a large Dutch community pharmacy-based prescription database (IADB.nl). RESULTS Since a peak of 9.8 users per 1000 youths in 2009, prevalence rates stabilized. Dosages in milligram per kilogram declined for the most frequently prescribed antipsychotic drugs during the study period. The median duration of use was 6.0 (95% CI 5.4-6.6) months. Boys used antipsychotic drugs significantly longer than girls, with a median of 6.9 (95% CI 6.1-7.7) versus 4.6 (95% CI 3.9-5.3) months (p < 0.01). Of the youths prescribed antipsychotics, 12.4% used them for at least 48 months. The majority of youths had used other psychotropic agents in the year before the start of an antipsychotic drug (62.4% in 2005 and 64.7% in 2015). CONCLUSIONS Despite a stabilization of usage rates and decline in dosages and duration of use, one in eight youths still used antipsychotic drugs for 4 years or longer. A substantial share of youths may, therefore, be at high risk for serious side effects.
Anesthesia & Analgesia
M edical procedures often evoke pain, distress, and anxiety. 1 Especially in children, these feel... more M edical procedures often evoke pain, distress, and anxiety. 1 Especially in children, these feelings not only severely affect comfort levels during medical procedures but are also associated with adverse consequences, such as attempts to escape, 2 poor recovery, 3 eating and sleeping disturbances, 3 and posttraumatic stress symptoms. 4 Furthermore, as pain and anxiety can lead to avoidance of health care, 5,6 interventions are needed to address pain and anxiety in pediatric patients. Distraction is a commonly applied intervention during medical procedures. For example, the use of music 7,8 and movies 9,10 has been proven efficacious in reducing pain and anxiety. Virtual reality (VR) is a relatively new technique to provide distraction and might be more effective than traditional methods. VR consists of a computer-generated environment, in which orientation and 3-dimensional interaction are possible. This environment is projected right in front of the user's eyes via advanced head-mounted displays (HMDs), including a wide field of view and motion tracking systems. 11 VR can create full immersion, which is a feeling of presence in the virtual environment. 11,12 Importantly, more immersion is related to more pain reduction, because BACKGROUND: Medical procedures often evoke pain and anxiety in pediatric patients. Virtual reality (VR) is a relatively new intervention that can be used to provide distraction during, or to prepare patients for, medical procedures. This meta-analysis is the first to collate evidence on the effectiveness of VR on reducing pain and anxiety in pediatric patients undergoing medical procedures. METHODS: On April 25, 2018, we searched EMBASE, MEDLINE, CENTRAL, PubMed, Web of Science, and PsycINFO with the keywords "VR," "children," and "adolescents." Studies that applied VR in a somatic setting with participants ≤21 years of age were included. VR was defined as a fully immersive 3-dimensional environment displayed in surround stereoscopic vision on a head-mounted display (HMD). We evaluated pain and anxiety outcomes during medical procedures in VR and standard care conditions. RESULTS: We identified 2889 citations, of which 17 met our inclusion criteria. VR was applied as distraction (n = 16) during venous access, dental, burn, or oncological care or as exposure (n = 1) before elective surgery under general anesthesia. The effect of VR was mostly studied in patients receiving burn care (n = 6). The overall weighted standardized mean difference (SMD) for VR was 1.30 (95% CI, 0.68-1.91) on patient-reported pain (based on 14 studies) and 1.32 (95% CI, 0.21-2.44) on patient-reported anxiety (based on 7 studies). The effect of VR on pediatric pain was also significant when observed by caregivers (SMD = 2.08; 95% CI, 0.55-3.61) or professionals (SMD = 3.02; 95% CI, 0.79-2.25). For anxiety, limited observer data were available. CONCLUSIONS: VR research in pediatrics has mainly focused on distraction. Large effect sizes indicate that VR is an effective distraction intervention to reduce pain and anxiety in pediatric patients undergoing a wide variety of medical procedures. However, further research on the effect of VR exposure as a preparation tool for medical procedures is needed because of the paucity of research into this field.
Critical Care
Backgrounds: Reports of increasing incidence rates of delirium in critically ill children are rea... more Backgrounds: Reports of increasing incidence rates of delirium in critically ill children are reason for concern. We evaluated the measurement properties of the pediatric delirium component (PD-scale) of the Sophia Observation Withdrawal Symptoms scale Pediatric Delirium scale (SOS-PD scale). Methods: In a multicenter prospective observational study in four Dutch pediatric ICUs (PICUs), patients aged ≥ 3 months and admitted for ≥ 48 h were assessed with the PD-scale thrice daily. Criterion validity was assessed: if the PD-scale score was ≥ 4, a child psychiatrist clinically assessed the presence or absence of PD according to the Diagnostic and statistical manual of mental disorders (DSM)-IV. In addition, the child psychiatrist assessed a randomly selected group to establish the false-negative rate. The construct validity was assessed by calculating the Pearson coefficient (r p) for correlation between the PD-scale and Cornell Assessment Pediatric Delirium (CAP-D) scores. Interrater reliability was determined by comparing paired nurse-researcher PD-scale assessments and calculating the intraclass correlation coefficient (ICC). Results: Four hundred eighty-five patients with a median age of 27.0 months (IQR 8-102) were included, of whom 48 patients were diagnosed with delirium by the child psychiatrist. The PD-scale had overall sensitivity of 92.3% and specificity of 96.5% compared to the psychiatrist diagnosis for a cutoff score ≥4 points. The r p between the PD-scale and the CAP-D was 0.89 (CI 95%, 0.82-0.93; p < 0.001). The ICC of 75 paired nurse-researcher observations was 0.99 (95% CI, 0.98-0.99). Conclusions: The PD-scale has good reliability and validity for early screening of PD in critically ill children. It can be validly and reliably used by nurses to this aim.
Therapeutic Drug Monitoring
To the Editors: We thank Peter Zweipfenning for his comments and remarks about our article by Klo... more To the Editors: We thank Peter Zweipfenning for his comments and remarks about our article by Kloosterboer et al1 entitled “Dried blood spot analysis for therapeutic drug monitoring of antipsychotics: drawbacks of its clinical application.” We agree that the conversion of dried blood spot (DBS) concentrations to estimated plasma concentrations is essential for clinical interpretation. First, Zweipfenning points out the use of the EMA guideline Bioanalytical Method Validation.2 This guideline focuses on the validation of bioanalytical methods in general and was indeed not developed specifically for DBS method validation. New regulatory guidelines finally start recognizing DBS as a relevant matrix only until recently.3 Unfortunately, to our knowledge, currently, there is no specific guideline with explicit criteria for the clinical validation of DBS methods. The EMA guideline, however, clearly addresses the requirements for crossvalidation (see section 4.3., page 10), ie, the comparison of data obtained from different methods. As our clinical validation study compares the DBS sampling method and venous sampling method, the EMA criteria are applicable. These criteria have also been used for DBS method validation in the literature previously.4 An international working group, with participation of the corresponding author, is currently developing a guideline for clinical validation of DBS methods. Second, the use of formula 1 is questioned. We agree that this formula can only be applied when the partition into blood cells is negligible,5 as is explained in our article. A low blood:serum ratio and high protein binding correspond to a negligible concentration in red blood cells, which both apply to the antipsychotics under study. The blood:serum ratios were previously reported by Patteet et al, as referenced in our article under no. 10. In this study, a blood:serum ratio of 0.6 for risperidone, 0.7 for its metabolite, and 0.7 for aripiprazole was reported.6 In general, a blood:serum ratio of 0.6–0.7 can be considered low because a theoretical range of 0.3–2 can be expected.7 We anticipate that the metabolite of aripiprazole has a similar affinity to blood cells because its log P value is comparable and the molecular structure is nearly identical to aripiprazole.8 The same probably applies for pipamperone because all antipsychotics are analyzed in plasma and have similar properties. Furthermore, Peter Zweipfenning elaborates about the margin of error in this ratio. The confidence intervals in the before mentioned study vary between 0 and 0.1 and can thus be interpreted as a low margin of error. Therefore, in our opinion, the blood:serum ratios, in combination with high protein binding, justify the use of formula 1. This formula has been applied in the same way in DBS validation studies previously.9
Therapeutic drug monitoring, Jun 1, 2018
Dried blood spot (DBS) sampling offers a minimally invasive sampling method for therapeutic drug ... more Dried blood spot (DBS) sampling offers a minimally invasive sampling method for therapeutic drug monitoring of antipsychotics. To facilitate implementation in clinical practice, the aim of this study was to perform a clinical validation study of a DBS method for quantification of risperidone, aripiprazole, pipamperone, and their major metabolites 9-OH risperidone and dehydro-aripiprazole in a real-life, clinical setting. Paired DBS and venous plasma samples were analyzed (n = 35 for risperidone, n = 21 for aripiprazole, n = 21 for pipamperone). Estimated plasma concentrations were calculated from DBS concentrations based on hematocrit and/or Deming regression formulas. Deming regression and Bland-Altman analyses were used to determine the agreement between the calculated and measured plasma concentrations. For Bland-Altman analysis, the following acceptance limit was used: for a minimum of 67% of the samples, the difference of the 2 measurements should be within 20% of their mean. T...
Journal of affective disorders, Apr 1, 2018
Anxiety disorders are highly prevalent during adolescence. Although literature points out that an... more Anxiety disorders are highly prevalent during adolescence. Although literature points out that anxiety symptoms are related to problems in social and academic functioning, the extent of these problems among adolescents with clinical anxiety disorders has not been systematically reviewed before. Electronic databases were searched up to October 2017, with keywords representing anxiety disorders, adolescents, and social or academic functioning. The inclusion criteria were studies with a sample of adolescents (10-19 years) with anxiety disorders that provided data regarding their social or academic functioning. 3431 studies were examined, of which 19 met the inclusion criteria. Adolescents with anxiety disorders had a lower social competence relative to their healthy peers. They reported more negativity within interpersonal relationships, higher levels of loneliness, and victimization. Most adolescents with anxiety disorders felt impaired at school, however, findings of their average sc...
Therapeutic Drug Monitoring
Background: Risperidone, aripiprazole, and pipamperone are antipsychotic drugs frequently prescri... more Background: Risperidone, aripiprazole, and pipamperone are antipsychotic drugs frequently prescribed for the treatment of comorbid behavioral problems in children with autism spectrum disorders. Therapeutic drug monitoring (TDM) could be useful to decrease side effects and to improve patient outcome. Dried blood spot (DBS) sample collection seems to be an attractive technique to develop TDM of these drugs in a pediatric population. The aim of this work was to develop and validate a DBS assay suitable for TDM and home sampling. Methods: Risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone were extracted from DBS and analyzed by ultra–high-performance liquid chromatography–tandem mass spectrometry using a C18 reversed-phase column with a mobile phase consisting of ammonium acetate/formic acid in water or methanol. The suitability of DBS for TDM was assessed by studying the influence of specific parameters: extraction solution, EDTA carryover, hematocrit, punching location, spot volume, and hemolysis. The assay was validated with respect to conventional guidelines for bioanalytical methods. Results: The method was linear, specific without any critical matrix effect, and with a mean recovery around 90%. Accuracy and imprecision were within the acceptance criteria in samples with hematocrit values from 30% to 45%. EDTA or hemolysis did not skew the results, and no punching carryover was observed. No significant influence of the spot volume or the punch location was observed. The antipsychotics were all stable in DBS stored 10 days at room temperature and 1 month at 4 or −80°C. The method was successfully applied to quantify the 3 antipsychotics and their metabolites in patient samples. Conclusions: A UHPLC-MS/MS method has been successfully validated for the simultaneous quantification of risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone in DBS. The assay provided good analytical performances for TDM and clinical research applications.